POS0180 THE EFFICACY AND SAFETY OF A FIXED-DOSE COMBINATION OF APOCYNIN AND PAEONOL IN SYMPTOMATIC KNEE OA: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL
Authors: A.R. Bihlet, I. Byrjalsen, J.R. Andersen, A. Metnik, A. Reynolds, N. Larkins, P. Alexandersen, H. Rovsing, U. Schmidt, R. Moots, P.G. Conaghan
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> There is a great unmet need for the development of effective treatments to treat the symptoms of OA. Nuclear-Factor Kappa-B (NF-κB) and Nrf2 play a key roles in OA pathogenesis and have been identified as potential targets. A fixed-dose combination of apocynin and paenol in a ratio of 2:7 (APPA) has been shown to inhibit activation of NF-κB and upregulate Nrf2. [1] <h3>Objectives</h3> We report the results of a phase 2a study evaluating the efficacy and safety of APPA in patients with symptomatic knee OA. <h3>Methods</h3> The trial was a 28-day randomized, placebo-controlled, double-blind study comparing 800 mg of APPA twice daily with matched placebo capsules. Patients with radiographic knee OA KL-grade 2-3, and a WOMAC pain score ≥40 and ≤90/100 of target knee at screening and baseline were randomized 1:1 to APPA or placebo. Main exclusion criteria included recent intraarticular surgery or injection therapy, hip pain greater than the target knee, and BMI ≥40 kg/m<sup>2</sup>. The primary endpoint was change from baseline to Day 28 in the WOMAC pain score. Safety outcomes included reported adverse events (AE), clinical laboratory parameters, ECG, and vital signs. A pre-defined subgroup analysis in subjects with a baseline PainDETECT score &gt;12 indicated a positive effect. Accordingly, post-hoc analyses were undertaken to further assess the effects of APPA in subgroups of participants with higher disease severity. <h3>Results</h3> 152 participants were randomized, and 149 (98%) completed the trial. The mean (SD) WOMAC pain score at baseline was 55.3 (10.2). The two groups were comparable in terms of baseline pain score, gender, age, and BMI. The primary endpoint was not met, mean difference (MD) between APPA and placebo was -0.89 (95 % CI: -5.62, 3.84, p=0.71, Figure 1A). Similarly, no significant differences were found on other key secondary endpoints (WOMAC Function and WOMAC total Figure 1B and C, respectively.) APPA was well tolerated and no differences in frequencies of reported AEs were noted, apart from a higher proportion of subjects reporting mild to moderate gastrointestinal discomfort reported with APPA compared to placebo (12% vs. 6.5 %). In the pre-defined subgroup of participants with baseline PainDETECT ≥ 13 (N=45), the difference in mean change in pain from baseline favored the APPA-group (MD: -11.20, 95 % CI: -20.29 to -2.11, p=0.02). Analysis of participants &gt; 50 WOMAC pain at baseline (Group 1, N=95, Figure 1D), and a KL-grade of the non-target knee &gt;2 (Group 2, N=105, Figure 1E), and a combination of these two criteria (Group 3, N=64, Figure 1F) found a positive effect of APPA compared to placebo (Group 1 MD: -2.61, 95 % CI: -8.98 to 3.76, p=0.42, Group 2 MD: -4.01, 95 % CI: -9.35 to 1.33, p=0.14, and Group 3 MD: -8.32, 95 % CI: -15.48 to -1.16, p=0.02). <h3>Conclusion</h3> Treatment with APPA 800 mg twice daily for 28 days in patients with symptomatic knee OA overall was not associated with significantly improved outcomes compared to placebo. The treatment was well-tolerated and safe. Subgroup analyses, however, showed a significant effect of APPA in patients with moderate to severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted. <h3>References</h3> [1]Cross AL, Hawkes J, Wright HL, Moots RJ, Edwards SW. APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling. Inflammopharmacology. 2020 Oct; 28(5):1223-1235. <h3>Disclosure of Interests</h3> Asger Reinstrup Bihlet Shareholder of: NBCD A/S, Employee of: NBCD A/S, Inger Byrjalsen Employee of: NBCD A/S, Jeppe Ragnar Andersen Shareholder of: NBCD A/S, Employee of: NBCD A/S, Anna Metnik Shareholder of: NBCD A/S, Employee of: NBCD A/S, Alan Reynolds Shareholder of: AKL R&amp;D, Employee of: AKL R&amp;D, Nicholas Larkins Shareholder of: AKL R&amp;D, Employee of: AKL R&amp;D, Peter Alexandersen: None declared, Helene Rovsing: None declared, Ulla Schmidt: None declared, Robert Moots Speakers bureau: Pfizer, Amgen, Novartis, Gilead, Grant/research support from: University of Liverpool received grant support from AKL on Phase 1 trial where Prof. Rob Moots was principal investigator. UoL also received grant support from AKL on basic neutrophil research., Philip G Conaghan Speakers bureau: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB, Consultant of: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB